1-Acyloxy(lower) alkyl-3-substituted pyrrolidine derivatives and process for preparing same

ABSTRACT

Disclosed are certain 3-(10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5-ylidene)-pyrrolidines and analogues thereof as well as processes for their preparation and their use as antitremorine agents.

1:51 States Patent [191 llmio et a1.

[ 1 .llnly 8,1975

[73] Assignee: Fujisawa Pharmaceutical Co., LtdL,

Osaka, Japan [22] Filed: Mar. l, 1973 [21] App]. No.: 336,942

[52] US. Cl. 260/326.33; 260/326.34; 424/274 [51} Int. Cl. C07d 70/04; C07d 27/04 [58] Fieldl of Search 260/326.33, 326.34

[56] References Cited OTHER PUBLICATIONS Noller, Chemistry of Organic Compounds, (1965 pp. 183-184.

Umio et al., Chem. Abs, Vol. 77: 147449b, (1972).

Primary Examiner1Richard J. Gallagher [57] ABSTRACT Disclosed are certain 3-( 10,1 l-dihydro-Sl-ldibenzo(a,d)cyclohepten-S-ylidene)-pyrrolidines and analogues thereof as well as processes for their preparation and their use as anti-tremorine agents.

9 Claims, N0 Drawings ll-ACYLOXYlLOWER) ALKYL-3-SUBSTITTJTED PYRROLIDTNE DERIVATIVES AND PROCESS ll Ulllt PREPARING SAME This invention relates to l-acyloxy(lovver)-alkyl-3 substituted pyrrolidine derivatives and the process for preparing same. Particularly the invention pertains to 1-acyloxy(lower)alkyl-3-substituted pyrrolidine derivatives represented by the general formula wherein A is an ethylene or oxygen linkage, X and X; are individually hydrogen or halogen, R is hydrogen or a lower alkyl group, R is a lower alkylene group and R is a lower alkyl or aryl group which may be substituted with one to three lower alkoxy groups, and acid addition salts thereof. The invention further pertains to a process for preparing the same.

ln the specification and claims, the term lower means a l to 8 carbon chain in an alkyl, alkylene and alkoxy groups, alkyl group means a straight or branched alkyl chain such as methyl, ethyl, propyl, isopropyl, butyl, etc., alkylene group means a straight or branched alkylene chain such as methylene, ethylene, propylene, isopropylene, etc., alkoxy group means methoxy, ethoxy, propoxy, etc., aryl group means phenyl, tolyl, xylyl, etc., and halogen means fluorine, chlorine, bromine or iodine.

The l-acyloxy(lower)alkyl-3-substituted pyrrolidine derivatives represented by the formula (I), which are all new compounds, have an antitremorine activity and are useful as an antiParkinson agent.

The compounds (I) described in the present invention can be prepared by reacting as l-hydroxy- (lower)alkyl-3-substituted pyrrolidine derivative of the general formula jig-Oil I W T v wherein A, X X R and R are individually the same as defined above, or the salt thereof with a carboxylic acid of the general formula R COOll-l (Ill) wherein R is the same as defined above, or the reactive derivative at the carboxyl group thereof.

The salt of the starting compound (ll) means an acid addition salt thereof with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, etc. or an organic acid such as maleic acid, tartaric acid, citric acid, picric acid, etc. Exemplars of the reactive derivative at the carboxyl group of the carboxylic acid (III) are an acid halides, acid anhydrides, amides, an azide and esters of the carboxylic acid (Ill), and the like. Examples of the said derivatives frequently used are acid halides such as acid chloride, acid bromide; acid azide; mixed anhydrides with dialkylphosphoric acid, dibenzylphosphoric acid, halogenophosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2- ethylbutanoic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid), or symmetrical type acid anhydride; acid amide with imidazole, 4-substituted imidazole, etc., and esters such as methyl ester, ethyl ester, cyanomethyl ester, p-nitrophenyl ester, pentachlorophenyl ester, 2,4,5-trichlorophenyl ester, propargyl ester, carboxymethyl thioester, pyranyl ester, methoxymethyl ester, phenylthio ester or N- hydroxysuccinimide ester, etc.

In the present reaction, the carboxylic acid (Ill) may also be used in the form of salts thereof. The salts of the carboxylic acid (III) to be usd may include the salts with an alkali metal such as sodium, potassium, etc., an alkaline earth metal such as calcium, magnesium, etc. or with an organic base such as ammonia, an amine (e.g. dimethylamine, trimethylamine, etc.).

The present reaction is advantageously carried out in the presence of a condensing agent such as N,N'- dicyclohexylcarbodiimide, N-cyclohexyl-N- morpholinoethylcarbodiimide, N-cyclohexyl-N-(4- diethylaminocyclohexyl)carbodiimide, N,l\l-diethylcarbodiimide, N,l l-diisopropylcarbodiimide, N-ethyl- N-(3-dimethylaminopropyl)carbodiimide, N,N- carbonyldi(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketone-N- cyclohexylimine, alkoxyacetylene, l -alkoxyl chloroethylene, 2-ethyl-7-hydroxybenzisoxazolium salt, and Z-ethyl-S-(m-sulfonyl)-isoxazolium hydroxide intramolecular salt.

The reaction of the present invention may be carried out either in or in the absence of a solvent. Exemplars of the solvent are ether, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetrahydrofurane, ethyl acetate and pyridine, and any other conventional organic solvents, which do not take part in the reaction, are also usable.

The present reaction may also be effected in the presence of a base such as an alkali metal bicarbonate, trialkylamine, pyridine or the like. When the base or the aforesaid condensing agent is in the form of liquid, they may be used simultaneously as the solvent used in the present reaction. The reaction temperature is not particularly critical, and the reaction may be effected either with cooling or at room temperature or with heating. The reaction product is recovered and purifled, according to conventional procedure, by extraction and isolation. The compound (K) may be converted, according to conventional procedure, into acid addition salts thereof with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, etc. or an organic acid such as acetic acid, propionic acid, succinic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, citric acid, etc.

The compounds (I) and its salts show an antitremorine activity, as shown with the following .test.

Antitremorine Test in Mice Antitrcmor (ED mg/kg) Test Compound Antitremor Antisalivation l-( 2-Acetoxycthyl )-2- methyl-3-( 10. l l-dihydro- 5H-dibcnzo[ a,d lcyclo- 0.3 3 6.5

heptcn-S-ylidenc) pyrrolidine In practical administration for a therapeutical purpose, the salts of the compounds (I) is to be employed in'a form'of pharmaceutically acceptable acid addition salts.

The'compounds (I) and their pharmaceutically acceptable salts can be administered by the conventional methods, the conventional types of unit dosages or with the conventional pharmaceutical carriers to produce a minor tra'nquilizing effect in human beings. I

Thus, th'ey can be' used in the form of pharmaceutical preparatioi'n'which" contain them in admixture with a pharmaceutical org'anic or inorganic carrier material suitable for enteral or parenteral applications. Oral ad- Example 2 pyrrolidineethanol is dissolved in 20 cc of chloroform.

, To the solutionis added, -g. ofisobutyryl chloride,

7 and theresulting mixture ish'e'ated under reflux for 19 hours.-. From the reaction liquid, the chloroform and isobutyryl chloride are removed by distillation under reduced pressure to obtain 15.7 g. of syrup as a residue. To the residue is added an aqueous sodium carbonate solution, and the resulting mixture is extracted with benzene. The benzene layer is washed with water and ministration bythe use of tablets, capsules or inliquid form such as suspensions, solutions or emulsions is particularly advantageous.

'- Practical 'and presently-preferred embodiments of r the present invention are illustrative shown in the following Examples.

s Example 1 l r l4..5:-:-.-.. Grams of 3-(10,l l-dihydro-Sl-ldibenzo[a,d]cyc1ohepten 5-y1idene )-2-methyll [a,d]cycloheptenylidene)pyrrolidine as oily substance. This product is converted, according to usual procedure, into the corresponding hydrochloride, and the pyrrolidineethanol is converted, according to usual procedure, into the corresponding hydrochloride. To the hydrochloride is added an excess of acetyl chloride, and the resulting mixture is heated under reflux for 2 hours. The liquid reaction mixture in .distilled to removean excess acetyl chloride, and the residue is washed with ether. The residue is further recrystallized from an ether-methanol mixture to obtain crystals of l-( Z-acetoxyethyl )-2-methyl-3-( 10,1 l-dihydro-S-l-ldibenzo[a,d]cyclohepten-5-ylidene)-pyrrolidine, m.p.- 192-193C., in 80% yield.

Elementary analysis: for C H NO C H N Calculated 72.43 7.09 3.52 I Found 71.96 6.88

then treated with 10% hydrochloric acid. The solvent is distilled off from the benzene layer to obtain crystals of l-( 2-isobutyryloxyethyl )-2-methyl-3-( 10,1 1- dihydro-51-l-dibenzo[a,d]cyclohepten-5- ylidene)pyrrolidine hydrochloride, m.p. l17-1l9C., in 61% yield. I

Elementary analysis: for C l-l No Cl C H N Calculated 73.30 7.57 3.29 Found 73.04 7.47 3.26

Example 3 4.8 Grams of 3-( 10,1 l-dihydro-SH- dibenzo[a,d]d]cyclohepten-5-ylidene)-2-methyl-1- pyrrolidineethanol is dissolved in 25 cc of anydrous benzene. To the solution is added a mixture comprising 7 7.0 g. of 3,4,5-trimethoxybenzoyl chloride 3.0 g. of triethylamine and 15 cc of dimethylformamide, and the resulting mixture is heated under reflux for 15 hours.

From the reaction liquid, the benzene and triethylamine are distilled off under reduced pressure, and the residue is added with benzene and washed with water and dried. The benzene is distilled off. The oily residue is subjected to alumina column chromatography and developed with benzene. The benzene is distilled off to obtain 5.5 g. of 1-{2-(3,4,5-trimethoxybenzoyl)- 1 oxyethyl}-2-methyl-3(10,1 l-dihydro-5 H-dibenzohydrochloride is recrystallized from a chloroformacetone mixture to obtain the crystalline hydrochloride salt 'of the present product, m.p. l93-l95C.

Elementary analysis: for C H NOQCI C H N Calculated 69.87 6.60 2.55 Found 69.74 I 6.53 s 2.71

Example 4 To 0.2 g of a-methyl-3-(l0,1l-dihydro-SH- dibenzo[a,dlcycloheptene-S-ylidene) 2-methyll pyrrolidineethanol to added 5 cc of acetyl chloride, and the resulting mixture is "heated under reflux for 15 hours. From. the reaction'liquid; excess acetyl chloride Elementary analysis: for C -,H;, NO ,Cl

Calculated 72.89 7.34 3.40 Found 72.61 7.50 3.31

Example 5 To a mixed solution of 0.5 g of 3-(10,1l-dihydro-5l-ldibenzo[a,d]cyclohepten-S-ylidene)-2-ethyl-1- pyrrolidineethanol and 0.46 g of triethylamine in 3 cc of dry chloroform are added with ice cooling a solution of 0.18 g of acetyl chloride in 2 cc of dry chloroform, and the resulting mixture is stirred at room temperature for 16 hours. The reaction liquid is pale orange in color at the beginning, but the color changes to reddish orange after completion of the reaction. Thereafter, the chloroform is distilled off, and the residue is charged with water and extracted with ether. The ethereal layer is thoroughly washed with water and then dried. The ether is removed by distillation from the ethereal layer to obtain a reddish orange oily product. The oily product is subjected to separation and purification by means of alumina (neutral) column chromatography (developing solvent: benzene) to obtain 0.2 g of l-(2-acetoxyethyl)-2-ethyl-3-(10,1 l-dihydro-SH- dibenzo[a,d]cyclohepten-5-ylidene)pyrrolidine as a yellow oily product. A solution of 0.2 g of this oily product in ether is treated with maleic acid, according to usual procedure, to convert said oily product into the corresponding maleate. The maleate is recrystallized three times from acetone to obtain colorless powder of 1-(2-acetoxyethyl)-2-ethyl-3-( 10,1 l-dihydro' Sl-l-dibenzo[a,d]cyclohepten-S-ylidene)pyrrolidine maleate, m.p. 158159C.

Example 6 To a mixed solution of 0.7 g of 3-( 10,1 l-dihydro-Sl-ldibenzo[a,d]cyclohepten-5-ylidene)-2-isopropyl-1- pyrrolidineethanol and 0.815 g of triethylamine in 4 cc of dry chloroform is added with ice cooling a solution of 0.673 g of acetyl chloride in 2 cc of dry chloroform, and the mixture is stirred at room temperature for 6 hours. The reaction liquid is pale orange in color at the initiation of the reaction, but the color of said reaction liquid changes to reddish orange after completion of the reaction. Thereafter, the chloroform is distilled off, and the residue is charged with water and extracted with ether. The ethereal layer is thoroughly washed with water, then dried and the ether is distilled off to obtain a reddish brown oily product. This oily product is subjected to separation and purification by means of alumina (neutral) column chromatography (developing solvent: benzene) to obtain 0.5 g of 1-(2- acetoxyethyl)-2-isopropyl-3-( 10,1 l-dihydro-Sl-idibenzo[a,d]-cyclohepten-5-ylidene) pyrrolidine as a yellow oily product.

This yellow oily product is dissolved in ether, and the solution is treated with maleic acid, according to usual procedure, to convert said oily product into the corresponding maleate. The maleate is recrystallized three times from an acetone-ether mixture to obtain colorless needles of 1-(2-acetoxyethyl)-2-isopropyl-3-(10,1 ldihydro-5ll-dibenzo[a,d]cyclohepten-5- ylidene)pyrrolidine maleate.

Elementary analysis: for C H O N C H N Calculated 71.26 6.98 2.77 Found 71.31 6.89 2.65

Example 7 To a mixed solution of 0.5 g of 3-(3-chloro-10,l l-

dihydro-5l-l-dibenzo[a,d]cyclohepten-5-ylidene)-2- methyl-l-pyrrolidineethanol and 0.57 g of triethylamine in 3 cc of dry chloroform is added with ice cooling a solution of 0.33 g of acetyl chloride in 2 cc of dry chloroform, and the resulting mixture is stirred at room temperature for 6 hours. The reaction liquid is pale orange in color at the time of initiation of the reaction, but the color changes to reddish orange after completion of the reaction. Thereafter, the chloroform is distilled off, and the residue is charged with water and extracted with ether. The ethereal layer is thoroughly washed with water and then dried, and the ether is distilled off to obtain a reddish brown oily product. This oily product is subjected to separation and purification by means of alumina (neutral) column chromatography (developing solvent: benzene) to obtain 0.3 g of 1-(2-acetoxyethyl)-2-methyl-3-(3-chloro-10,1 1- dihydro-S H-dibenzo[a,d]cyclohepten-5- ylidene)pyrrolidine as a yellow oily product.

This oily product is dissolved in ether and treated with maleic acid, according to usual procedure, to convert said product into the corresponding maleate. The maleate is recrystallized twice from an acetone-ether mixture and then once from an anhydrous ethanolanhydrous ether mixture to obtain colorless granules of l-( 2-acetoxyethyl)-2-methyl-3-(3-chloro-10,l ldihydro-5l-l-dibenzo[a,d]cyclohepten-5- ylidene)pyrrolidine maleate, m;p. 143144C.

Elementary analysis: for C H O NCI To a mixed solution of 0.35 g of 3-(9ll-l-xanthen-9- ylidene)-2-methyl-l-pyrrolidineethanol and 0.58 g of triethylamine in 3 cc of dry chloroform is dropped a solution of 0.38 g acetyl chloride in 2 cc dry chloroform,

whereupon the reaction liquid is stirred at roomtemperature for 6. hours, whereby crystals precipitate.

After completion of the reaction, the reaction liquid is charged with water and extracted with ether. The ethereal-layer is washed with water and then dried, and the ether is distilled off, to obtain an oil as residue. This oil is subjected to separation and purification by means of alumina chromatography (developing solvent: ethyl acetate) to obtain a yellow oil of l-(2-acetoxyethyl)-2- v methyl-3-(9H-xanthen-9-ylidene)-pyrrolidine.

This yellow oil is dissolved in ether and the solution is treated, according to usual procedure, with an ethanol solution of oxalic acid, to convert said oil into the corresponding oxalate. The oxalate is recrystallized from ethanol to obtain pale yellow granules of oxalate of the product, m.p. 201C.

Elementary analysis: for C H NO- H O Calculatcd (7z Found What we claim is: l. A compound of the formula 8 wherein A is ethylene or'oxygen, I

R is hydrogen or lower alkyl, R is lower alkylene, 7 a

" R is lower alkyl, phenyl or'p'lflenyl substituted with l-(2-Acetoxyethyl)-2-methy l-3-(9H-xanthen-9- 

1. A COMPOUND OF THE FORMULA
 2. 1-(2-Acetoxyethyl)-2-methyl-3-(10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5-ylidene)-pyrrolidine.
 3. 1-(2-Isobutyryloxyethyl)-2-methyl-3-(10,11-dihydro-5H -dibenzo(a,d)cyclohepten-5-ylidene)pyrrolidine.
 4. 1-(2-(3,4,5-trimethoxybenzoyl)oxyethyl)-2-methyl-3-(10,11-dihydro-5H -dibenzo(a,d)cyclohepten-5-ylidene)pyrrolidene.
 5. 1-(2-Acetoxypropyl)-2-methyl-3-(10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5-ylidene)-pyrrolidine.
 6. 1-(2-Acetoxyethyl)-2-ethyl-3-(10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5-ylidene)-pyrrolidine.
 7. 1-(2-Acetoxyethyl)-2-isopropyl-3-(10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5-ylidene)-pyrrolidine.
 8. 1-(2-Acetoxyethyl)-2-methyl-3-(3-chloro-10,11-dihydro-5H -dibenzo(a,d)cyclohepten-5-ylidene)-pyrrolidine.
 9. 1-(2-Acetoxyethyl)-2-methyl-3-(9H-xanthen-9-ylidene)pyrrolidine. 